Primary lateral sclerosis (PLS) is a rare, sporadic upper motor neuron disorder thought to be a variant of the amyotrophic lateral sclerosis (ALS) family of motor neuron disorders. In PLS, motor neurons of the spinal cord and brainstem are clinically spared, in contrast to ALS patients. PLS patients typically have a normal lifespan, surviving more than a decade after symptoms begin. In this natural history study that began in FY2000, we previously showed that the rate of progression was most rapid in the first years after symptoms begin, often reaching a plateau after seven to eight years. This clinical course suggests that there may be a limited time window during which corticospinal neurons degenerate, and when potential interventions should be targeted. Unfortunately, making the diagnosis of PLS relies on clinical criteria that require symptoms to be present for 3-5 years without development of lower motor neuron signs. In the first several years of symptoms, clinical signs alone do not allow distinction between PLS and amyotrophic lateral sclerosis (ALS). A biomarker to help identify patients with PLS in the first years of symptoms is needed. Previous work from our group had found particular neuroimaging changes in patients with long-standing, established PLS. These included changes in diffusion tensor imaging (DTI) of white matter tracts emanating from the motor cortex, gradual thinning of the motor cortex, and reorganization of functional connectivity with the cerebellum. When such imaging findings emerge during the course of symptoms in PLS is unknown. To see whether neuroimaging findings occur earlier than PLS can be diagnosed clinically, we collected clinical data and MRI scans on a cohort of patients with pre-PLS symptoms for 5 years or less. We followed their clinical course beyond 5 years of symptoms to see if they would meet clinical criteria for the diagnosis PLS. The same imaging battery of structural and functional data was also acquired on patients with longstanding, established PLS and a cohort of healthy controls. The analysis of this data is complete and has been submitted for publication in FY18. A second study in this project is exploring genetic causes or contributions to PLS. In FY17, whole genome sequencing was completed for 50 genomes: seven trios (PLS patients and both parents) and twenty-nine individuals). Analysis of the sequences are ongoing by a collaborator, Dr. Bryan Traynor in the National Institute of Aging.